Behaviors in children as young as age 3 predict substance use and substance use disorders (SUDs) in adolescence and adulthood. Little is known, however, about the neurobiological processes that underlie this risk. We will test a neurobehavioral model of SUDs that accounts for their familial transmission and characterizes putative externalizing (antisocial) and internalizing (anxious and depressed) pathways to SUDs via the neurobehavioral constructs of effortful control (EC), reward responsiveness (RR), and fear proneness (FP). Our hypothesis is that this Big 3 represents heritable, early emerging neurobehavioral processes that underlie non-specific risk for SUDs. To test this model, we will integrate brain science with a longitudinal-family design of two cohorts of children (aged 3-7 and 8-12) and their parents. Even more unique is that the parents have already been studied since early childhood as part of an ongoing family study, the Michigan Longitudinal Study (MLS). The original MLS parents (generation 1 [G1]) have high rates of SUDs (60%), and the original offspring participants (G2) are now adults, who also have high rates of SUDs, and many are now raising children of their own (G3). We will recruit the G3 families (N =259 children) to complete a comprehensive assessment of each neurobehavioral liability that includes neurophysiological (error-related negativity [ERN] for EC, feedback-related negativity [FRN] for RR, and fear-potentiated startle for FP), laboratory-based objective tasks, interview, and questionnaire approaches. We have three specific aims. (1) Examine the family transmission of the Big 3. The multigenerational structure of the sample also allows for especially unique comparisons such as the similarity between G2 parents and their G3 children using measures taken at the same chronological ages. (2) Test the unique, additive, and interactive effects of the Big 3 on risk for SUDs in the G3 offspring and their relationship to SUDs in G2 parents. We predict that different profiles of high and low levels of the Big 3 will differentiate externalizin and internalizing pathways to SUDs. We will also test whether the family transmission of the Big 3 mediates the associations between parent and child indices of SUDs. (3) Conduct a follow-up assessment of each child cohort 3 years after baseline to test whether the Big 3 have prospective and concurrent associations with intermediate phenotypes for SUD risk assessed at follow-up (e.g., substance initiation, externalizing problems). Delineating the mechanisms of early emerging neurobehavioral risk and the nature of the family transmission of risk will have a significant impact in regards to understanding etiological processes that will inform early intervention efforts to prevent the emergence and long-term impact of SUDs.